Despite dramatic progress, too many patients still die of cancer. Survivors often suffer from the short and long-term effects of cytotoxic/genotoxic treatments. My vision is that future cancer treatments will combine approaches that destroy cancers by intelligent focusing of the patient's own immune system, with less dependence on toxic modalities. Immunotherapy (ImmRx) is being increasingly integrated into cancer treatment, with many examples of benefit. As clinically evident cancer has escaped from a patient's immune system, effective treatment should provide the immune system with the ability to recognize a tumor it previously ignored. This can be achieved by the use of monoclonal antibody (mAb)-based agents that recognize structures selectively expressed on tumors cells. My team has made substantial contributions to basic, translational and clinical cancer ImmRx. We demonstrated that anti-tumor mAbs use endogenous innate immune cells (mainly NK cells) to initiate tumor selective antibody dependent cell-mediated cytotoxicity (ADCC) in vitro and tumor destruction in vivo. Simultaneous activation of cells responsible for ADCC synergizes with antitumor mAb-therapy. In the clinical trials we led, combinations of tumor-reactive mAbs and innate-immune activators were clinically active and are now the standard of care for pediatric neuroblastoma (NBL). Our analyses of patients' samples revealed how immune networks are activated, and how they may influence treatment efficacy. For example, we showed how these combination treatments can promote ADCC. Recently, using serum samples from a NBL trial, we identified an antibody in some patients, prior to any mAb treatment, directed against the therapeutic mAb. This endogenous antibody was associated with better clinical outcome. We are pursuing this finding, as it may provide ways to positively impact mAb therapy. In our mouse models, initial tumor destruction via innate immune ADCC induced a subsequent adaptive T cell response; addition of checkpoint blockade further augmented the adaptive response resulting in eradication of advanced murine tumors. Additional mouse studies led to the hypothesis that tumors escape ADCC by turning off NK cells through inhibitory NK receptors. This hypothesis was tested in patients receiving mAb (to induce ADCC). We found that patients with favorable NK receptor/ligand genotypes have better outcomes. The combinatory approach we are now pursuing involves mAb-directed activation of innate (NK and macrophages) immunity, induction of adaptive immunity, use of next generation mAb-based agents, and incorporation of genetic analyses of responsible NK receptors and their ligands. This strategy builds on the findings, momentum, and strengths of my team and our collaborations. We will systematically test, integrate and develop these concepts. Our goal is to develop life saving regimens that combine off the shelf agents and genetic evaluation to decrease the morbidity and mortality of cancer worldwide.